OBJECTIVE:

The recurrence risk of autism spectrum disorders (ASD) is estimated to be between 3% and 10%, but previous research was limited by small sample sizes and biases related to ascertainment, reporting, and stoppage factors. This study used prospective methods to obtain an updated estimate of sibling recurrence risk for ASD.

METHODS:

A prospective longitudinal study of infants at risk for ASD was conducted by a multisite international network, the Baby Siblings Research Consortium. Infants (n = 664) with an older biological sibling with ASD were followed from early in life to 36 months, when they were classified as having or not having ASD. An ASD classification required surpassing the cutoff of the Autism Diagnostic Observation Schedule and receiving a clinical diagnosis from an expert clinician.

RESULTS:

A total of 18.7% of the infants developed ASD. Infant gender and the presence of >1 older affected sibling were significant predictors of ASD outcome, and there was an almost threefold increase in risk for male subjects and an additional twofold increase in risk if there was >1 older affected sibling. The age of the infant at study enrollment, the gender and functioning level of the infant's older sibling, and other demographic factors did not predict ASD outcome.

CONCLUSIONS:

The sibling recurrence rate of ASD is higher than suggested by previous estimates. The size of the current sample and prospective nature of data collection minimized many limitations of previous studies of sibling recurrence. Clinical implications, including genetic counseling, are discussed.

Background

It has been shown that amyloid ß (Aβ), a product of proteolytic cleavage of the amyloid β precursor protein (APP), accumulates in neuronal cytoplasm in non-affected individuals in a cell type–specific amount.

Methodology/Principal Findings

In the present study, we found that the percentage of amyloid-positive neurons increases in subjects diagnosed with idiopathic autism and subjects diagnosed with duplication 15q11.2-q13 (dup15) and autism spectrum disorder (ASD). In spite of interindividual differences within each examined group, levels of intraneuronal Aβ load were significantly greater in the dup(15) autism group than in either the control or the idiopathic autism group in 11 of 12 examined regions (p<0.0001 for all comparisons; Kruskall-Wallis test). In eight regions, intraneuronal Aβ load differed significantly between idiopathic autism and control groups (p<0.0001). The intraneuronal Aβ was mainly N-terminally truncated. Increased intraneuronal accumulation of Aβ17–40/42 in children and adults suggests a life-long enhancement of APP processing with α-secretase in autistic subjects. Aβ accumulation in neuronal endosomes, autophagic vacuoles, Lamp1-positive lysosomes and lipofuscin, as revealed by confocal microscopy, indicates that products of enhanced α-secretase processing accumulate in organelles involved in proteolysis and storage of metabolic remnants. Diffuse plaques containing Aβ1–40/42 detected in three subjects with ASD, 39 to 52 years of age, suggest that there is an age-associated risk of alterations of APP processing with an intraneuronal accumulation of a short form of Aβ and an extracellular deposition of full-length Aβ in nonfibrillar plaques.

Conclusions/Significance

The higher prevalence of excessive Aβ accumulation in neurons in individuals with early onset of intractable seizures, and with a high risk of sudden unexpected death in epilepsy in autistic subjects with dup(15) compared to subjects with idiopathic ASD, supports the concept of mechanistic and functional links between autism, epilepsy and alterations of APP processing leading to neuronal and astrocytic Aβ accumulation and diffuse plaque formation.

Background

Individuals with Autism Spectrum Disorders (ASD) typically show impaired eye contact during social interactions. From a young age, they look less at faces than typically developing (TD) children and tend to avoid direct gaze. However, the reason for this behavior remains controversial; ASD children might avoid eye contact because they perceive the eyes as aversive or because they do not find social engagement through mutual gaze rewarding.

Methods

We monitored pupillary diameter as a measure of autonomic response in children with ASD (n = 20, mean age = 12.4) and TD controls (n = 18, mean age = 13.7) while they looked at faces displaying different emotions. Each face displayed happy, fearful, angry or neutral emotions with the gaze either directed to or averted from the subjects.

Results

Overall, children with ASD and TD controls showed similar pupillary responses; however, they differed significantly in their sensitivity to gaze direction for happy faces. Specifically, pupillary diameter increased among TD children when viewing happy faces with direct gaze as compared to those with averted gaze, whereas children with ASD did not show such sensitivity to gaze direction. We found no group differences in fixation that could explain the differential pupillary responses. There was no effect of gaze direction on pupil diameter for negative affect or neutral faces among either the TD or ASD group.

Conclusions

We interpret the increased pupillary diameter to happy faces with direct gaze in TD children to reflect the intrinsic reward value of a smiling face looking directly at an individual. The lack of this effect in children with ASD is consistent with the hypothesis that individuals with ASD may have reduced sensitivity to the reward value of social stimuli.

Background

Language delay is a hallmark feature of autism spectrum disorders (ASD). The identification of word boundaries in continuous speech is a critical first step in language acquisition that can be accomplished via statistical learning and reliance on speech cues. Importantly, early word segmentation skills have been shown to predict later language development in typically developing (TD) children.

Methods

Here we investigated the neural correlates of online word segmentation in children with and without ASD with a well-established behavioral paradigm previously validated for functional magnetic resonance imaging. Eighteen high-functioning boys with ASD and 18 age- and IQ-matched TD boys underwent functional magnetic resonance imaging while listening to two artificial languages (containing statistical or statistical + prosodic cues to word boundaries) and a random speech stream.

Results

Consistent with prior findings, in TD control subjects, activity in fronto-temporal-parietal networks decreased as the number of cues to word boundaries increased. The ASD children, however, did not show this facilitatory effect. Furthermore, statistical contrasts modeling changes in activity over time identified significant learning-related signal increases for both artificial languages in basal ganglia and left temporo-parietal cortex only in TD children. Finally, the level of communicative impairment in ASD children was inversely correlated with signal increases in these same regions during exposure to the artificial languages.

Conclusions

This is the first study to demonstrate significant abnormalities in the neural architecture subserving language-related learning in ASD children and to link the communicative impairments observed in this population to decreased sensitivity to the statistical and speech cues available in the language input.

Background

Infants and preschoolers with ASD show impairment in their responses to other people's distress relative to children with other developmental delays and typically developing children. This deficit is expected to disrupt social interactions, social learning, and the formation of close relationships. Response to distress has not been evaluated previously in infants with ASD earlier than 18 months of age.

Methods

Participants were 103 infant siblings of children with autism and 55 low-risk controls. All children were screened for ASD at 36 months and 14 were diagnosed with ASD. Infants' responsiveness to distress was evaluated at 12, 18, 24, and 36 months. An examiner pretended to hit her finger with a toy mallet and infants' responses were video-recorded. Attention to the examiner and congruent changes in affect were coded on four-point Likert scales.

Results

Cross-sectional and longitudinal analyses confirm that the ASD group paid less attention and demonstrated less change in affect in response to the examiner's distress relative to the high-risk and low-risk participants who were not subsequently diagnosed with ASD. Group differences remained when verbal skills and general social responsiveness were included in the analytic models.

Conclusions

Diagnostic groups differ on distress response from 12 to 36 months of age. Distress-response measures are predictive of later ASD diagnosis above and beyond verbal impairments. Distress response is a worthwhile target for early intervention programs.

Abnormal eye contact is a core symptom of autism spectrum disorders (ASD), though little is understood of the neural bases of gaze processing in ASD. Competing hypotheses suggest that individuals with ASD avoid eye contact due to the anxiety-provoking nature of direct eye gaze or that eye-gaze cues hold less interest or significance to children with ASD. The current study examined the effects of gaze direction on neural processing of emotional faces in typically developing (TD) children and those with ASD. While undergoing functional magnetic resonance imaging (fMRI), 16 high-functioning children and adolescents with ASD and 16 TD controls viewed a series of faces depicting emotional expressions with either direct or averted gaze. Children in both groups showed significant activity in visual-processing regions for both direct and averted gaze trials. However, there was a significant group by gaze interaction such that only TD children showed reliably greater activity in ventrolateral prefrontal cortex for direct versus averted gaze. The ASD group showed no difference between direct and averted gaze in response to faces conveying negative emotions. These results highlight the key role of eye gaze in signaling communicative intent and suggest altered processing of the emotional significance of direct gaze in children with ASD.

Longitudinal research into adult outcomes in autism remains limited. Unlike previous longitudinal examinations of adult outcome in autism, the twenty participants in this study were evaluated across multiple assessments between early childhood (M = 3.9 years) and adulthood (M = 26.6 years). In early childhood, responsiveness to joint attention (RJA), language, and intelligence were assessed. In adulthood, the parents of participants responded to interviews assessing the adaptive functioning, autistic symptomology and global functioning of their children. RJA and early childhood language predicted a composite measure of adult social functioning and independence. Early childhood language skills and intelligence predicted adult adaptive behaviors. RJA predicted adult non-verbal communication, social skills and symptoms. Adaptive behaviors changed with development, but symptoms of autism did not. Additional factors associated with adult outcomes are discussed.

Objective

To replicate the factor structure and predictive validity of revised Autism Diagnostic Observation Schedule algorithms in an independent dataset (N = 1,282).

Method

Algorithm revisions were replicated using data from children ages 18 months to 16 years collected at 11 North American sites participating in the Collaborative Programs for Excellence in Autism and the Studies to Advance Autism Research and Treatment.

Results

Sensitivities and specificities approximated or exceeded those of the old algorithms except for young children with phrase speech and a clinical diagnosis of pervasive developmental disorders not otherwise specified.

Conclusions

Revised algorithms increase comparability between modules and improve the predictive validity of the Autism Diagnostic Observation Schedule for autism cases compared to the original algorithms.

Functional neuroimaging studies of face processing deficits in autism have typically focused on visual processing regions, such as the fusiform face area (FFA), which have shown reduced activity in autism spectrum disorders (ASD), though inconsistently. We recently reported reduced activity in the inferior frontal region in ASD, implicating impaired mirror-neuron systems during face processing. In the present study, we used fMRI during a face processing task in which subjects had to match faces presented in the upright versus inverted position. Typically developing (TD) children showed a classic behavioral inversion effect, increased reaction time for inverted faces, while this effect was significantly reduced in ASD subjects. The fMRI data showed similar responses in the fusiform face area for ASD and TD children, with both groups demonstrating increased activation for inverted faces. However, the groups did differ in several brain regions implicated in social cognition, particularly prefrontal cortex and amygdala. These data suggest that the behavioral differences in processing upright versus inverted faces for TD children are related not to visual information processing but to the social significance of the stimuli. Our results are consistent with other recent studies implicating frontal and limbic dysfunction during face processing in autism.

Autism is currently viewed as a spectrum condition including strikingly different severity levels. IQ is consistently described as one of the primary aspects of the heterogeneity in autism. To investigate the possibility of more than one distinct subtype of autism based on IQ, both latent class analysis and taxometric methods were used to classify Mullen IQ scores in a sample of children with autism spectrum disorder (N=456). Evidence for multiple IQ-based subgroups was found using both methods. Groups differed in level of intellectual functioning and patterns of verbal versus nonverbal ability. Results support the notion of distinct subtypes of autism which differ in severity of intellectual ability, patterns of cognitive strengths and weaknesses, and severity of autism symptoms.

Autism spectrum disorders (ASDs) represent a group of childhood neurodevelopmental and neuropsychiatric disorders characterized by deficits in verbal communication, impairment of social interaction, and restricted and repetitive patterns of interests and behaviour. To identify common genetic risk factors underlying ASDs, here we present the results of genome-wide association studies on a cohort of 780 families (3,101 subjects) with affected children, and a second cohort of 1,204 affected subjects and 6,491 control subjects, all of whom were of European ancestry. Six single nucleotide polymorphisms between cadherin 10 (CDH10) and cadherin 9 (CDH9)—two genes encoding neuronal cell-adhesion molecules—revealed strong association signals, with the most significant SNP being rs4307059 (P = 3.4 × 10−8, odds ratio = 1.19). These signals were replicated in two independent cohorts, with combined P values ranging from 7.4 × 10−8 to 2.1 × 10−10. Our results implicate neuronal cell-adhesion molecules in the pathogenesis of ASDs, and represent, to our knowledge, the first demonstration of genome-wide significant association of common variants with susceptibility to ASDs.

Siblings of probands with autism spectrum disorders are at higher risk for developing the broad autism phenotype (BAP). We compared the linguistic abilities (i.e., pragmatic language, school achievements, and underling reading processes) of 35 school-age siblings of children with autism (SIBS-A) to those of 42 siblings of children with typical development. Results indicated lower pragmatic abilities in a subgroup of SIBS-A identified with BAP related difficulties (SIBS-A-BAP) whereas school achievements and reading processes were intact. Furthermore, among SIBS-A-BAP, significant negative correlations emerged between the severity scores on the Autism Diagnostic Observation Schedule and full and verbal IQ scores. These results are discussed in the context of the developmental trajectories of SIBS-A and in relation to the BAP.

Objective

To examine prospectively the emergence of behavioral signs of autism in the first years of life in infants at low and high risk for autism.

Method

A prospective longitudinal design was used to compare 25 infants later diagnosed with an autism spectrum disorder (ASD) with 25 gender-matched low-risk children later determined to have typical development. Participants were evaluated at 6, 12, 18, 24, and 36 months of age. Frequencies of gaze to faces, social smiles, and directed vocalizations were coded from video and rated by examiners.

Results

The frequency of gaze to faces, shared smiles, and vocalizations to others were highly comparable between groups at 6 months of age, but significantly declining trajectories over time were apparent in the group later diagnosed with ASD. Group differences were significant by 12 months of age on most variables. Although repeated evaluation documented loss of skills in most infants with ASD, most parents did not report a regression in their child’s development.

Conclusions

These results suggest that behavioral signs of autism are not present at birth, as once suggested by Kanner, but emerge over time through a process of diminishment of key social communication behaviors. More children may present with a regressive course than previously thought, but parent report methods do not capture this phenomenon well. Implications for onset classification systems and clinical screening are also discussed.

Objective

To study the relationship between parent concerns about development in the first year and a half of life and later autism diagnostic outcomes.

Method

Parent concerns about development were collected for infants at high and low risk for autism, using a prospective, longitudinal design. Parents were asked about developmental concerns at study intake and when their infant was 6, 12, and 18 months. Infants were then followed up until 36 months, when diagnostic status was determined.

Results

By the time their child was 12 months, parents who have an older child with autism reported significantly more concerns in autism spectrum disorders-related areas than parents of children with typical outcomes. These concerns were significantly related to independent measures of developmental status and autism symptoms and helped predict which infants would later be diagnosed with autism or autism spectrum disorders. At 6 months, however, the concerns of parents who have an older child with autism do not predict outcome well.

Conclusion

Explicitly probing for parent concerns about development is useful for identifying children in need of closer monitoring and surveillance, as recommended by the American Academy of Pediatrics.

We investigated whether deficits in social gaze and affect and in joint attention behaviors are evident within the first year of life among siblings of children with autism who go on to be diagnosed with autism or ASD (ASD) and siblings who are non-diagnosed (NoASD-sib) compared to low-risk controls. The ASD group did not differ from the other two groups at 6 months of age in the frequency of gaze, smiles, and vocalizations directed toward the caregiver, nor in their sensitivity to her withdrawal from interaction. However, by 12 months, infants in the ASD group exhibited lower rates of joint attention and requesting behaviors. In contrast, NoASD-sibs did not differ from comparison infants on any variables of interest at 6 and 12 months.

With increased public awareness of the early signs and recent American Academy of Pediatrics recommendations that all 18- and 24-month-olds be screened for autism spectrum disorders, there is an increasing need for diagnostic assessment of very young children. However, unique challenges exist in applying current diagnostic guidelines for autism spectrum disorders to children under the age of 2 years. In this article, we address challenges related to early detection, diagnosis, and treatment of autism spectrum disorders in this age group. We provide a comprehensive review of findings from recent studies on the early development of children with autism spectrum disorders, summarizing current knowledge on early signs of autism spectrum disorders, the screening properties of early detection tools, and current best practice for diagnostic assessment of autism spectrum disorders before 2 years of age. We also outline principles of effective intervention for children under the age of 2 with suspected/confirmed autism spectrum disorders. It is hoped that ongoing studies will provide an even stronger foundation for evidence-based diagnostic and intervention approaches for this critically important age group.

We observed infant siblings of children with autism later diagnosed with ASD (ASD siblings; n = 17), infant siblings of children with autism with and without other delays (Other Delays and No Delays siblings; n = 12 and n = 19, respectively) and typically developing controls (TD controls; n = 19) during a free-play task at 18 months of age. Functional, symbolic, and repeated play actions were coded. ASD siblings showed fewer functional and more non-functional repeated play behaviors than TD controls. Other Delays and No Delays siblings showed more non-functional repeated play than TD controls. Group differences disappeared with the inclusion of verbal mental age. Play as an early indicator of autism and its relationship to the broader autism phenotype is discussed.

Autism spectrum disorders have been associated with maternally derived duplications that involve the imprinted region on the proximal long arm of chromosome 15. Here we describe a boy with a chromosome 15 duplication arising from a 3:1 segregation error of a paternally derived translocation between chromosome 15q13.2 and chromosome 9q34.12, which led to trisomy of chromosome 15pter-q13.2 and 9q34.12-qter. Using array comparative genome hybridization, we localized the breakpoints on both chromosomes and sequence homology suggests that the translocation arose from non-allelic homologous recombination involving the low copy repeats on chromosome 15. The child manifests many characteristics of the maternally-derived duplication chromosome 15 phenotype including developmental delays with cognitive impairment, autism, hypotonia and facial dysmorphisms with nominal overlap of the most general symptoms found in duplications of chromosome 9q34. This case suggests that biallelically expressed genes on proximal 15q contribute to the idic(15) autism phenotype.

Objective To compare the relative long-term benefit of family-focused cognitive behavioral therapy (FCBT) and child-focused cognitive behavioral therapy (CCBT) for child anxiety disorders at a 1-year follow-up. Method Thirty-five children (6–3 years old) randomly assigned to 12–16 sessions of family-focused CBT (FCBT) or child-focused CBT (CCBT) participated in a 1-year follow-up assessment. Independent evaluators, parents, and children rated anxiety and parental intrusiveness. All were blind to treatment condition and study hypotheses. Results Children assigned to FCBT had lower anxiety scores than children assigned to CCBT on follow-up diagnostician- and parent-report scores, but not child-report scores. Exploratory analyses suggested the advantage of FCBT over CCBT may have been evident more for early adolescents than for younger children and that reductions in parental intrusiveness may have mediated the treatment effect. Conclusion FCBT may yield a stronger treatment effect than CCBT that lasts for at least 1 year, although the lack of consistency across informants necessitates a circumspect view of the findings. The potential moderating and mediating effects considered in this study offer interesting avenues for further study.

We compared the cognitive and language development at 4, 14, 24, 36, 54 months, and 7 years of siblings of children with autism (SIBS-A) to that of siblings of children with typical development (SIBS-TD) using growth curve analyses. At 7 years, 40% of the SIBS-A, compared to 16% of SIBS-TD, were identified with cognitive, language and/or academic difficulties, identified using direct tests and/or parental reports. This sub-group was identified as SIBS-A-broad phenotype (BP). Results indicated that early language scores (14–54 months), but not cognitive scores of SIBS-A-BP and SIBS-A-nonBP were significantly lower compared to the language scores of SIBS-TD, and that the rate of development was also significantly different, thus pinpointing language as a major area of difficulty for SIBS-A during the preschool years.

The genetics underlying the autism spectrum disorders (ASDs) is complex and remains poorly understood. Previous work has demonstrated an important role for structural variation in a subset of cases, but has lacked the resolution necessary to move beyond detection of large regions of potential interest to identification of individual genes. To pinpoint genes likely to contribute to ASD etiology, we performed high density genotyping in 912 multiplex families from the Autism Genetics Resource Exchange (AGRE) collection and contrasted results to those obtained for 1,488 healthy controls. Through prioritization of exonic deletions (eDels), exonic duplications (eDups), and whole gene duplication events (gDups), we identified more than 150 loci harboring rare variants in multiple unrelated probands, but no controls. Importantly, 27 of these were confirmed on examination of an independent replication cohort comprised of 859 cases and an additional 1,051 controls. Rare variants at known loci, including exonic deletions at NRXN1 and whole gene duplications encompassing UBE3A and several other genes in the 15q11–q13 region, were observed in the course of these analyses. Strong support was likewise observed for previously unreported genes such as BZRAP1, an adaptor molecule known to regulate synaptic transmission, with eDels or eDups observed in twelve unrelated cases but no controls (p = 2.3×10−5). Less is known about MDGA2, likewise observed to be case-specific (p = 1.3×10−4). But, it is notable that the encoded protein shows an unexpectedly high similarity to Contactin 4 (BLAST E-value = 3×10−39), which has also been linked to disease. That hundreds of distinct rare variants were each seen only once further highlights complexity in the ASDs and points to the continued need for larger cohorts.

Author Summary

Autism spectrum disorders (ASDs) are common neurodevelopmental syndromes with a strong genetic component. ASDs are characterized by disturbances in social behavior, impaired verbal and nonverbal communication, as well as repetitive behaviors and/or a restricted range of interests. To identify genes likely to contribute to ASD etiology, we performed high density genotyping in 912 multiplex families from the Autism Genetics Resource Exchange (AGRE) collection and contrasted results to those obtained for 1,488 healthy controls. To enrich for variants most likely to interfere with gene function, we restricted our analyses to deletions and gains encompassing exons. Of the many genomic regions highlighted, 27 were seen to harbor rare variants in cases and not controls, both in the first phase of our analysis, and also in an independent replication cohort comprised of 859 cases and 1,051 controls. More work in a larger number of individuals will be required to determine which of the rare alleles highlighted here are indeed related to the ASDs and how they act to shape risk.

Background

Maternally-derived duplications that include the imprinted region on the proximal long arm of chromosome 15 underlie a complex neurobehavioral disorder characterized by cognitive impairment, seizures and a substantial risk for autism spectrum disorders[1]. The duplications most often take the form of a supernumerary pseudodicentric derivative chromosome 15 [der(15)] that has been called inverted duplication 15 or isodicentric 15 [idic(15)], although interstitial rearrangements also occur. Similar to the deletions found in most cases of Angelman and Prader Willi syndrome, the duplications appear to be mediated by unequal homologous recombination involving low copy repeats (LCR) that are found clustered in the region. Five recurrent breakpoints have been described in most cases of segmental aneuploidy of chromosome 15q11-q13 and previous studies have shown that most idic(15) chromosomes arise through BP3:BP3 or BP4:BP5 recombination events.

Results

Here we describe four duplication chromosomes that show evidence of atypical recombination events that involve regions outside the common breakpoints. Additionally, in one patient with a mosaic complex der(15), we examined homologous pairing of chromosome 15q11-q13 alleles by FISH in a region of frontal cortex, which identified mosaicism in this tissue and also demonstrated pairing of the signals from the der(15) and the normal homologues.

Conclusion

Involvement of atypical BP in the generation of idic(15) chromosomes can lead to considerable structural heterogeneity.

Understanding the intended meaning of a remark beyond what is explicitly stated is an integral part of successful social interactions. Here, we examined the neural circuitry underlying the interpretation of communicative intent in children and adults using irony comprehension as a test case. Participants viewed cartoon drawings while listening to short scenarios ending with a potentially ironic remark and were asked to decide whether the speaker was being sincere or ironic. In both children and adults, instructions to attend to the cues provided by the speaker's facial expression or tone of voice modulated the activity in visual and language cortices, respectively. Overall, children engaged the medial prefrontal cortex and left inferior frontal gyrus more strongly than adults, whereas adults recruited the fusiform gyrus, extrastriate areas and the amygdala more strongly than children. Greater involvement of prefrontal regions in children may subserve the integration of multiple cues to reconcile the discrepancy between the literal and intended meaning of an ironic remark. This developmental shift from a reliance on frontal regions to posterior occipitotemporal regions may reflect the automatization of basic reasoning about mental states. This study is the first to examine developmental changes in the neural circuitry underlying natural language pragmatics.